Myxoma Virus and the Leporipoxviruses: An Evolutionary Paradigm

Abstract

Myxoma virus (MYXV) is the type species of the Leporipoxviruses, a genus of Chordopoxvirinae, double stranded DNA viruses, whose members infect leporids and squirrels, inducing cutaneous fibromas from which virus is mechanically transmitted by biting arthropods. However, in the European rabbit (Oryctolagus cuniculus), MYXV causes the lethal disease myxomatosis. The release of MYXV as a biological control for the wild European rabbit population in Australia, initiated one of the great experiments in evolution. The subsequent coevolution of MYXV and rabbits is a classic example of natural selection acting on virulence as a pathogen adapts to a novel host species. Slightly attenuated mutants of the progenitor virus were more readily transmitted by the mosquito vector because the infected rabbit survived longer, while highly attenuated viruses could be controlled by the rabbit immune response. As a consequence, moderately attenuated viruses came to dominate. This evolution of the virus was accompanied by selection for genetic resistance in the wild rabbit population, which may have created an ongoing co-evolutionary dynamic between resistance and virulence for efficient transmission. This natural experiment was repeated on a continental scale with the release of a separate strain of MYXV in France and its subsequent spread throughout Europe. The selection of attenuated strains of virus and resistant rabbits mirrored the experience in Australia in a very different environment, albeit with somewhat different rates. Genome sequencing of the progenitor virus and the early radiation, as well as those from the 1990s in Australia and Europe, has shown that although MYXV evolved at high rates there was no conserved route to attenuation or back to virulence. In contrast, it seems that these relatively large viral genomes have the flexibility for multiple pathways that converge on a similar phenotype.

Next step in the ongoing arms race between myxoma virus and wild rabbits in Australia is a novel disease phenotype

“…The second possibility is that rather than being a single key mutation, the acute collapse syndrome is caused by independent mutations in different viral lineages, such that there is convergence at the phenotypic level, but not the genetic level. There being multiple genetic routes to the same virulence phenotypes is a consistent feature of the radiation of the Australian (22,31,37) and European (38) MYXV lineages. For instance, the hypervirulent BRK 4/93, the most lethal of the viruses we tested, has only 2 unique nonsynonymous mutations outside M009L: a large deletion with probable loss of function in M036L and A47V in M112, a Holliday junction resolvase.…”

“…The simplest is that it is the result of a single key mutation. All the 1990s viruses tested here have reading frame disruptions in M009L, a member of a threegene family that encodes a putative E3 ubiquitin ligase (36), although this gene has not previously been reported to affect virulence (37). It is unclear how the loss of this gene could cause a gain of function (massive immunosuppression).…”

Benign Rabbit Caliciviruses Exhibit Evolutionary Dynamics Similar to Those of Their Virulent Relatives

“…Indeed, it is theoretically possible that RCV-A1 was introduced into Australia with MYXV. Early preparations of MYXV brought from the Rockefeller Institute in the United States to Australia were material that had been maintained by regular rabbit passage for over 40 years (27). If RCV was present in any rabbit used during passage, then it could have been present in the material harvested for virus preparations (3).…”

“…Prior to that, myxoma virus (MYXV) had been introduced into Australia in the 1950s to combat the ever-increasing rabbit population and was initially extremely effective (25,26). However, host-pathogen coevolution led to a combination of MYXV attenuation and mounting host resistance in Australian rabbits, which allowed a degree of reexpansion of the rabbit population (27).…”

Understanding Immunity through the Lens of Disease Ecology

“…There also occurred a co-evolutionary increased resistance in the wild rabbit population, presumably caused by the severe selective pressures of a highly lethal disease epidemic. In addition, there was some evidence for a resulting compensatory rebound of myxoma virulence [47] in a manner reminiscent of a “red queen” effect [48–52]. I note that these attempts at biological control did not eliminate the target population, nor could they.…”